Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin

Wysocki, Piotr J.; Wierusz‐Wysocka, Bogna

doi:10.1586/erm.10.22

Cited by 63 publications

(51 citation statements)

References 121 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…17) In addition, given that obesity, insulin resistance, and hyperinsulinemia may play roles in the onset of malignancies including breast cancer, this further supports the observations that metformin users have a low incidence of cancer. 19) AMPK activation has been shown to play a critical role in regulation of energy metabolism under both physiological and pathological conditions, and involves regulation of downstream pathways relevant to the control of cellular proliferation. 20) Therefore, because identification of new AMPK activators is essential for the development of anti-cancer agents, we investigated the effects of PA on AMPK activation.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Properties of Pomolic Acid-Induced AMP-Activated Protein Kinase Activation in MCF7 Human Breast Cancer Cells

Youn

Lee

et al. 2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes.Recent studies indicate that AMPK activation strongly suppresses cell proliferation in tumor cells, which requires high rates of protein synthesis and de novo fatty acid synthesis for their rapid growth. Pomolic acid (PA) has been previously described as being active in inhibiting the growth of cancer cells. In this study, we investigated PA activated AMPK, and this activity was related to proliferation and apoptosis in MCF7 breast cancer cells. PA inhibited cell proliferation and induced sub-G 1 arrest, elevating the mRNA levels of the apoptotic genes p53 and p21. PA activated caspase-3, -9, and poly(ADP-ribose) polymerase, and this effect was inhibited by z-VAD-fmk. AMPK activation was increased by treating cells with PA, inactivated by treating cells with a compound C, and co-treatment consisting of PA and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. These anti-cancer potentials of PA were accompanied by effects on de novo fatty acid synthesis as shown by the decreased expression of fatty acid synthase, and decreased acetyl-CoA carboxylase activation and incorporation of [ 3 H]acetyl-CoA into fatty acids. In addition, PA inhibited key enzymes involved in protein synthesis such as mammalian target of rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These results suggest that PA exerts anti-cancer properties through the modulation of AMPK pathways and its value as an anti-cancer agent in breast cancer therapy. Key words AMP-activated protein kinase; pomolic acid; breast cancerBioactive natural products provide structures that will become major sources of novel agents with pharmacological promise. 1) Among the well known anti-cancer drugs are the so-called vinca alkaloids (vinblastin and vincristine), isolated from Catharanthus roseus, and the podophylotoxins (etoposide and teniposide), which are semisynthetic derivatives of epipodophyllotoxin, extracted from Podophyllum peltatum.2)The anti-tumoral activities of certain di-and tri-terpenes have been reported. For instance, the di-terpene, Taxol (Paclitaxel), initially isolated from the bark of Taxus brevifolia, has provided a major renewable natural source of anti-cancer drugs which have displayed activity against several cancers. 3)Pomolic acid (PA), a pentacyclic triterpene, was highly effective in inhibiting the growth of leukemia cell lines.2) Apart from its capacity to induce apoptosis, the mechanisms of PA activity are presently unclear. As part of an evaluation of potential of new anti-cancer compounds, this study investigated the molecular pathways of PA-induced cell death, including apoptosis.AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel-sensing enzyme, is a heterotrimeric serine/ threonine protein kinase that is composed of a catalytic α-subunit and regulatory β-and γ-subunits. AMPK activity is allosterically...

show abstract

Section: Resultsmentioning

confidence: 99%

Anticancer Properties of Pomolic Acid-Induced AMP-Activated Protein Kinase Activation in MCF7 Human Breast Cancer Cells

Youn

Lee

et al. 2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…The concept of a relationship between dysregulated metabolism and carcinogenesis was first enunciated by Otto Warburg more than 80 years ago (Davison and Schafer 2010). There is now a large body of evidence supporting a link between obesity, metabolic syndrome, insulin resistance with increased risk of cancers Wysocki and Wierusz-Wysocka 2010). Type 2 diabetes and high level of circulating blood glucose have been shown to be positively correlated with increased breast cancer mortality (Bjorge et al 2010;Wolf et al 2005).…”

Section: Stromal Adipocytes In Obesity-associated Mammary Carcinogenesismentioning

confidence: 99%

Adipokines – Toward the Molecular Dissection of Interactions Between Stromal Adipocytes and Breast Cancer Cells

Fan¹,

Wang²

2011

Breast Cancer - Recent Advances in Biology, Imaging and Therapeutics

View full text Add to dashboard Cite

“…Hyperinsulinemia, IGF-1 and IGF-1 receptor (IGF-1R) levels are known to be important in OC development and progression [20][21][22][23] through interactions with the downstream PI3K/Akt/mTOR pathway [24][25][26][27]. Components of this pathway are often mutated, amplified, or aberrantly expressed in OCs, and are currently being targeted for OC treatment [28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Increased efficacy of metformin corresponds to differential metabolic effects in ovarian tumors in obese versus lean mice

Wysham

Zhong

Dickens

et al. 2016

Gynecologic Oncology

View full text Add to dashboard Cite

Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the K18-gT 121 +/-; p53 fl/ fl ; Brca1 fl/fl (KpB) mouse model, metformin inhibited tumor growth in both lean and obese mice. However, in the obese mice, metformin decreased tumor growth by 60%, whereas tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of metformin in obesity corresponded with inhibition of mitochondrial complex 1 and fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion, metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian tumors in obese mice have heightened susceptibility to metformin. www.impactjournals.com/oncotarget/

show abstract

Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin

Cited by 63 publications

References 121 publications

Anticancer Properties of Pomolic Acid-Induced AMP-Activated Protein Kinase Activation in MCF7 Human Breast Cancer Cells

Anticancer Properties of Pomolic Acid-Induced AMP-Activated Protein Kinase Activation in MCF7 Human Breast Cancer Cells

Adipokines – Toward the Molecular Dissection of Interactions Between Stromal Adipocytes and Breast Cancer Cells

Increased efficacy of metformin corresponds to differential metabolic effects in ovarian tumors in obese versus lean mice

Contact Info

Product

Resources

About